IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis
Open Access
- 10 December 2012
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 123 (1), 247-260
- https://doi.org/10.1172/jci63681
Abstract
IL-17–producing CD8+ T (Tc17) cells are detectible in multiple sclerosis (MS) lesions; however, their contribution to the disease is unknown. To identify functions of Tc17 cells, we induced EAE, a murine model of MS, in mice lacking IFN regulatory factor 4 (IRF4). IRF4-deficient mice failed to generate Tc17 and Th17 cells and were resistant to EAE. After adoptive transfer of WT CD8+ T cells and subsequent immunization for EAE induction in these mice, the CD8+ T cells developed a Tc17 phenotype in the periphery but could not infiltrate the CNS. Similarly, transfer of small numbers of WT CD4+ T cells alone did not evoke EAE, but when transferred together with CD8+ T cells, IL-17–producing CD4+ (Th17) T cells accumulated in the CNS and mice developed severe disease. Th17 accumulation and development of EAE required IL-17A production by CD8+ T cells, suggesting that Tc17 cells are required to promote CD4+ T cell–mediated induction of EAE. Accordingly, patients with early-stage MS harbored a greater number of Tc17 cells in the cerebrospinal fluid than in peripheral blood. Our results reveal that Tc17 cells contribute to the initiation of CNS autoimmunity in mice and humans by supporting Th17 cell pathogenicity.Keywords
This publication has 48 references indexed in Scilit:
- TH17 cytokines in autoimmune neuro-inflammationCurrent Opinion in Immunology, 2011
- Functional Specialization of Interleukin-17 Family MembersImmunity, 2011
- Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteriaAnnals of Neurology, 2011
- CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell helpNature, 2009
- Pathogenic MOG-reactive CD8+ T cells require MOG-reactive CD4+ T cells for sustained CNS inflammation during chronic EAEJournal of Neuroimmunology, 2009
- Autoimmune T cell responses in the central nervous systemNature Reviews Immunology, 2009
- Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responsesNature, 2009
- IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotypeProceedings of the National Academy of Sciences of the United States of America, 2008
- IRF-4-Binding Protein Inhibits Interleukin-17 and Interleukin-21 Production by Controlling the Activity of IRF-4 Transcription FactorImmunity, 2008
- Emerging concepts in CD8+ T regulatory cellsCurrent Opinion in Immunology, 2008